Human Gene Module / Chromosome X / HDAC8

HDAC8histone deacetylase 8

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 12
Rare Variants / Common Variants
7 / 0
EAGLE Score
3.7
Limited Learn More
Aliases
HDAC8, CDA07,  CDLS5,  HD8,  HDACL1,  MRXS6,  RPD3,  WTS
Associated Syndromes
Cornelia de Lange syndrome-5 (CDLS5), Cornelia de Lange syndrome 5
Chromosome Band
Xq13.1
Associated Disorders
ID
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Molecular Function

The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HDAC8 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle Deardorff MA , et al. (2012) No -
2 Support X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face Harakalova M , et al. (2012) No -
3 Support Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance Kaiser FJ , et al. (2014) No -
4 Support Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism Ansari M , et al. (2014) No -
5 Recent Recommendation Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement Kline AD , et al. (2018) No -
6 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No ID, speech delay
7 Support Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder Wang L et al. (2020) Yes -
8 Support - Hiraide T et al. (2021) No -
9 Support - Pode-Shakked B et al. (2021) No -
10 Support - Miyake N et al. (2023) Yes -
11 Support - Wang J et al. (2023) Yes -
12 Support - Erica Rosina et al. (2024) No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.675C>G p.Tyr225Ter stop_gained De novo - Unknown 33644862 Hiraide T et al. (2021)
c.1075C>T p.Pro359Ser missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.522C>A p.Tyr174Ter stop_gained De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.932C>T p.Thr311Met missense_variant De novo - Simplex 36973392 Miyake N et al. (2023)
c.697G>T p.Asp233Tyr missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.471T>G p.Asp157Glu missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.482del p.Tyr161SerfsTer18 frameshift_variant Familial Maternal Simplex 33023636 Wang L et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
S
icon
S

Score remained at S

Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
S
icon
S

Score remained at S

Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[New Scoring Scheme]
4/1/2019
S
icon
S

Score remained at S

Description

Mutations in the HDAC8 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-5; OMIM 300882) (Deardorff et al., 2012; Harakalova et al., 2012; Kaiser et al., 2014; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with HDAC8 mutations presented with autism spectrum disorder.

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019]
Krishnan Probability Score

Score 0.43153003625512

Ranking 20762/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.92270772467946

Ranking 3006/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92852370939365

Ranking 10936/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.4154454359874

Ranking 18508/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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